This project is aimed at understanding the role of enzyme systems in host immune defense, specifically the NADPH oxidase. We are interested in understanding the role of the NADPH oxidase in the generation and control of inflammation and its role in protection from infection. This work will be informative on how to manipulate the host immune system pharmacologically, immunologically, and genetically. We have used a mouse created in my laboratory that is deficient in the NADPH oxidase that closely mimics NADPH oxidase deficiency in humans, chronic granulomatous disease (CGD). In addition to our work on the NADPH oxidase, we are pursuing the underlying basis of another host defense defect, hyper-IgE and recurrent infection syndrome (Job syndrome or HIERIS). This is an autosomal dominant disease characterized by extremely elevated IgE, recurrent sino-pulmonary infections, osteopenia, kyphoscoliosis, pulmonary cysts, and dental abnormalities. Identification of the gene(s) involved will be critically important to our understanding of innate immunity, the host immune response, skeletal growth and development, and dental exfoliation. Once appropriate candidate genes are identified, they will be disrupted in mice and further studies will be carried out.